The Community Engaged Digital Alzheimer's Research (CEDAR) Study: A Digital Intervention to Increase Research Participation of Black American Participants in the Brain Health Registry.

BACKGROUND: Although Black/African American older adults bear significant inequities in prevalence, incidence, and outcomes of Alzheimer's disease and related dementias, they are profoundly under-included in Alzheimer's Disease research. Community-Engaged Research (e.g., equitable community/science partnerships) is an evidence-based approach for improving engagement of underrepresented populations into Alzheimer's Disease research, but has lacked scalability to the national level. As internet use among older adults from underrepresented populations continues to grow, internet-based research shows promise as a feasible, valid approach to engagement and longitudinal assessment. The Community Engaged Digital Alzheimer's Research (CEDAR) study utilizes a community-engaged research approach to increase the engagement and research participation of Black/African American adults in the Brain Health Registry (BHR) and Alzheimer Disease clinical research. OBJECTIVES: To describe the methods and evaluate the feasibility of the CEDAR culturally-informed digital platform within BHR. DESIGN: All Black/African American participants in BHR were invited to enroll in CEDAR and to consider serving on a newly convened Community-Scientific Partnership Board to guide the study. The community board guided the development a culturally-informed cadre of engagement materials and strategies to increase research participation. Engagement strategies included incentives for study task completion, culturally-informed communications (e.g., landing page, emails and social media), resources about brain health, and video and written testimonials by CEDAR participants. SETTING: BHR, an Internet-based registry and cohort. PARTICIPANTS: BHR participants self-identifying as Black/African American were invited to enroll. All participants who signed an online informed consent document were enrolled. MEASUREMENTS: We report the number of participants invited, enrolled, completed tasks, and volunteered to join the community board. We compared the demographics, cognitive profile, and baseline BHR task completion rates between CEDAR participants and all those invited to join the study. RESULTS: Of 3738 invited, 349 (9.34%) enrolled in CEDAR. 134 (37% of CEDAR participants) volunteered to join the community board, of which 19 were selected for the community board. Compared to those invited, the CEDAR cohort had a higher percentage of female participants (84.5%) and a lower percentage of participants who identify as belonging to more than one ethnocultural group (21.8%). Compared to those did not enroll in CEDAR, those enrolled in CEDAR had a higher percentage of participants completing all BHR tasks (22%) and a higher percentage of participants completing at least one cognitive test (76%). Those enrolled in CEDAR also had a higher percentage of participants having an enrolled study partner (18%). CONCLUSIONS: A culturally-informed Community-Engaged Research approach, including a remotely-convened community board, to engagement of Black/African American participants in an online research registry is feasible. This approach can be adapted for use in various clinical studies and other settings. Future studies will evaluate the effectiveness of the engagement strategies.

Understanding Online Registry Facilitators and Barriers Experienced by Black Brain Health Registry Participants: The Community Engaged Digital Alzheimer's Research (CEDAR) Study.

BACKGROUND: Failure of Alzheimer's disease and related diseases (ADRD) research studies to include and engage Black participants is a major issue, which limits the impact and generalizability of research findings. Little is known about participation of Black adults in online ADRD-related research registries. OBJECTIVES: As part of the Community Engaged Digital Alzheimer's Research (CEDAR) Study, this study aims to increase our understanding of facilitators and barriers of Black adults to participating in ADRD-related online registries, as well as to understand their preferences for communication channels. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: We invited all Black participants enrolled in the Brain Health Registry (BHR) to complete a cross-sectional online survey. The survey consisted of rating scales and open-text questions asking about their attitudes towards brain health research, reasons for joining and continuing to participate in BHR, difficulties with participating, and preferences for modes of contact and website usage. RESULTS: Of all invited Black BHR participants (N=3,636), 198 (5.5%) completed the survey. The mean age was 58.4 (SD=11.3), mean years of education were 16.3 (SD=2.4), and 85.5% identified as female. Reported facilitators for joining and continuing to participate in BHR were personal interest (e.g., learning more about own brain health) and altruism (e.g., helping research). Among additional registry features which could encourage return, receiving feedback or scores about BHR tasks was rated the highest. Of those who found BHR participation difficult (21%), the most frequent reason was time burden. The most preferred way of receiving study information was via email. Participants reported that the websites that they used the most were YouTube and Facebook. DISCUSSION: The results of our study can inform the development of culturally-responsive registry features and engagement efforts to improve inclusion and participation of Black adults in online ADRD research. Providing participants with feedback about their registry performance and reducing the number of registry tasks are among the recommended strategies.

BST-2 expression in human hepatocytes is inducible by all three types of interferons and restricts production of hepatitis C virus.

Bone marrow stromal cell antigen 2 (BST-2, also known as tetherin, CD317, or HM1.24) has recently been identified as a host restriction factor against diverse families of enveloped viruses. However, the effects of BST-2 on the life cycle of hepatitis C virus (HCV), an enveloped RNA virus, remain unclear and controversial. Here we demonstrated that human hepatocytes including Huh7.5.1 cells, primary human hepatocytes (PHHs), and HepG2 cells constitutively expressed low to moderate levels of endogenous BST-2 on the cell surface, which could be robustly up-regulated by all three types of interferons (IFNs) such as IFN-α, IFN-γ, and IFN-λ. IFN-α and IFN-γ showed a synergistic effect in induction of BST-2 expression on human hepatocytes. Over-expression of BST-2 by BST-2-expressing vector transfection or up-regulation of BST-2 by IFN stimulation markedly suppressed HCV production, whereas shRNA-mediated depletion of endogenous BST-2 significantly enhanced HCV production in infected Huh7.5.1 cells. IFN-mediated anti-HCV activity was partially but significantly diminished by shRNA-mediated knockdown of BST-2 expression, indicating that BST- 2 upregulation is directly involved in IFN-mediated inhibition of HCV production. We also found that both BST-2 and HCV core co-localized with intracellular lipid droplets (LDs), suggesting that BST-2-HCV interaction may take place around LDs as LDs constitute an important intracellular organelle for HCV assembly and replication. Taken together, our data suggest that BST-2 is a host restriction factor against HCV, and induction of BST-2 in hepatocytes could be one of the mechanisms by which current HCV standard therapy (IFN-α plus ribavirin) achieves a sustained virological response (SVR).

Updated research nosology for HIV-associated neurocognitive disorders.

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.

Effects of oxygen tension and supplements to the culture medium on activation and development of bovine follicles in vitro.

Our laboratory developed a method for culturing small pieces of bovine and baboon ovarian cortex, rich in primordial follicles, that supports the initiation of follicle growth and development to the primary stage. However, only a few follicles progressed to the secondary stage. The purpose of the current experiments was to determine if changes in culture conditions, specifically oxygen concentration and supplements to the culture medium, would facilitate the primary to secondary follicle transition. In Experiment 1, ovarian cortical pieces from late-gestation bovine fetuses were cultured with 2, 5, 20, or 60% oxygen in Waymouth's medium plus ITS+ (insulin, transferrin, selenium plus linoleic acid and BSA). Although the three lower concentrations of oxygen were generally equivalent in promoting follicle activation and growth, the highest concentration (60%) had deleterious effects on follicle survival after 7 days in culture, reducing the number of healthy follicles to about 35% of the number observed with 20% oxygen (P<0.05). In Experiment 2, bovine ovarian cortical pieces were cultured in the standard gas mixture (5% CO(2) in air) with graded doses of fetal bovine serum (FBS, 2.5, 5, or 10%) in the presence or absence of 0.5 or 1x ITS+. All concentrations of FBS alone were much less effective at maintaining follicular health and supporting the initiation and progression of follicular growth than was ITS+. However, 5 and 10% FBS alone increased the percentage of healthy primordial and primary follicles by about twofold (P<0.05) in the absence of ITS+ and in the presence of 0.5x ITS+, they enhanced the primary to secondary follicle transition by 10- and 9-fold, respectively. Thus, of the culture conditions evaluated, 20% oxygen and medium containing 0.5x ITS+ plus 5% or 10% FBS were the most effective for promoting follicular health and development.

Non-Hodgkin lymphoma and benzene exposure: a systematic literature review.

Epidemiological papers that address an association between benzene exposure and non-Hodgkin lymphoma (NHL) were identified and separated by study design. Eighteen studies contained 21 study groups-11 population-based case-control study groups, 3 nested occupation-based case-control study groups and 7 occupational benzene cohort study groups. Petroleum industry studies were not included. Only two of these 21 study groups showed statistically significant associations. However, these were among workers with multiple exposures across industries. Eleven of the 21 study groups presented ratios less than one, two equaled one, and eight were greater than one. Over all, about as many cases were observed (404) as expected (390.0) for an observed to expected ratio of 1.04 (0.94-1.14). After removal of the studies with multiple chemical exposures problems, the observed was 359 cases with 373.2 cases expected, yielding an odds ratio of 0.96 (0.86-1.06). Further assessment of an association with NHL should document the benzene exposure and separate out the contribution of non-benzene exposures.

Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells.

Adoptive T cell therapy, involving the ex vivo selection and expansion of antigen-specific T cell clones, provides a means of augmenting antigen-specific immunity without the in vivo constraints that can accompany vaccine-based strategies. A phase I study was performed to evaluate the safety, in vivo persistence, and efficacy of adoptively transferred CD8+ T cell clones targeting the tumor-associated antigens, MART1MelanA and gp100 for the treatment of patients with metastatic melanoma. Four infusions of autologous T cell clones were administered, the first without IL-2 and subsequent infusions with low-dose IL-2 (at 0.25, 0.50, and 1.0 x 10(6) unitsm(2) twice daily for the second, third, and fourth infusions, respectively). Forty-three infusions of MART1MelanA-specific or gp100-specific CD8+ T cell clones were administered to 10 patients. No serious toxicity was observed. We demonstrate that the adoptively transferred T cell clones persist in vivo in response to low-dose IL-2, preferentially localize to tumor sites and mediate an antigen-specific immune response characterized by the elimination of antigen-positive tumor cells, regression of individual metastases, and minor, mixed or stable responses in 8 of 10 patients with refractory, metastatic disease for up to 21 mo.

UNC-16, a JNK-signaling scaffold protein, regulates vesicle transport in C. elegans.

Transport of synaptic components is a regulated process. Loss-of-function mutations in the C. elegans unc-16 gene result in the mislocalization of synaptic vesicle and glutamate receptor markers. unc-16 encodes a homolog of mouse JSAP1/JIP3 and Drosophila Sunday Driver. Like JSAP1/JIP3, UNC-16 physically interacts with JNK and JNK kinases. Deletion mutations in Caenorhabditis elegans JNK and JNK kinases result in similar mislocalization of synaptic vesicle markers and enhance weak unc-16 mutant phenotypes. unc-116 kinesin heavy chain mutants also mislocalize synaptic vesicle markers, as well as a functional UNC-16::GFP. Intriguingly, unc-16 mutations partially suppress the vesicle retention defect in unc-104 KIF1A kinesin mutants. Our results suggest that UNC-16 may regulate the localization of vesicular cargo by integrating JNK signaling and kinesin-1 transport.

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma.

Understanding the pathology of familial pancreatic carcinoma may provide important insights into pancreatic tumorigenesis. We now describe in detail the pancreatic pathology of an autosomal dominant pancreatic carcinoma kindred with distinct clinical, genetic, and pathologic manifestations differing from all other reported forms of sporadic or familial pancreatic neoplasia. Affected individuals develop a prodrome of diabetes mellitus, pancreatic exocrine insufficiency, and characteristic pancreatic imaging abnormalities. Eleven family members have undergone total pancreatectomy, revealing a unique and characteristic fibrocystic, lobulocentric pancreatic atrophy. This was patchy to diffuse in distribution and was invariably associated with a nesidioblastosis-like endocrine cell hyperplasia. All but one resected pancreas demonstrated glandular epithelial dysplasia: 10 had low-grade dysplasia (pancreatic intraductal neoplasia grade II of III or PanIN II) and seven also had high-grade dysplasia (pancreatic intraductal neoplasia grade III of III or PanIN III). Dysplasia was multifocal in small-to medium-sized duct-like structures within areas of acinar atrophy, microcystic change, and mucinous hyperplasia. Two pancreata had carcinomas of multiple and unusual histologic subtypes, including small cell undifferentiated carcinoma and giant cell anaplastic carcinoma. The findings in this kindred yield important information on a distinctive and previously unrecognized pancreatic cancer precursor. Recognition of this entity may help identify additional kindreds and perhaps the underlying genetic defect. As is the case for other familial cancers, the as yet unknown specific genetic defect may have wider implications for pancreatic cancer in general.

Axillary web syndrome after axillary dissection.

BACKGROUND: Some patients undergoing axillary lymph node dissection (ALND) experience postoperative pain and limited range of motion associated with a palpable web of tissue extending from the axilla into the ipsilateral arm. The purpose of this study is to characterize the previously undescribed axillary web syndrome (AWS). METHODS: To identify patients with AWS, a retrospective review was performed of all invasive breast cancer patients treated by a single surgeon (REM) between 1980 and 1996. Records were also reviewed of 4 more recent patients who developed AWS after undergoing sentinel node lymph node dissection (SLND) without ALND. RESULTS: Among 750 sequentially treated patients, 44 (6%) developed AWS between 1 and 8 weeks after their axillary procedure. The palpable subcutaneous cords extended from the axillary crease down the ipsilateral arm, across the antecubital space, and in severe cases down to the base of the thumb. The web was associated with pain and limited shoulder abduction (< or = 90 degrees in 74% of patients). AWS resolved in all cases within 2 to 3 months. AWS also occurred after SLND. Tissue sampling of webs in 4 patients showed occlusion in lymphatic and venous channels. CONCLUSIONS: AWS is a self-limiting cause of morbidity in the early postoperative period. More limited axillary surgery, with less lymphovenous disruption, might reduce the severity and incidence of this syndrome, although SLND does not eliminate its occurrence.

Internal mammary lymph node drainage patterns in patients with breast cancer documented by breast lymphoscintigraphy.

BACKGROUND: Metastases to internal mammary lymph nodes (IMN) may occur in patients with breast cancer and may alter treatment recommendations. The purpose of this study was to identify the frequency of IMN drainage in patients undergoing breast lymphoscintigraphy and sentinel lymph node dissection (SLND). METHODS: The combined technique of peritumoral injection of radiocolloid and Lymphazurin blue for SLND was performed on 220 patients. All patients underwent preoperative lymphoscintigraphy before SLND. Lesion location by quadrant included: 110 upper outer (UOQ), 49 lower outer (LOQ), 30 upper inner (UIQ), 24 lower inner (LIQ), and 7 central. RESULTS: Drainage to any nodal basin was observed in 184 of 220 patients (84%). IMN drainage was documented in 37 of 220 (17%) of patients. IMN drainage without evidence of axillary drainage occurred in 2 of 220 patients(1%). Drainage to the IMN based on quadrant location of the lesion was as follows: UOQ, 10%; LOQ, 27%; UIQ, 17%; LIQ, 25%; and central, 29%. CONCLUSIONS: Internal mammary lymph node drainage shown by breast lymphoscintigraphy is common. Tumors in all quadrants may drain to IMNs, although drainage is significantly more common from quadrants other than the UOQ. Further studies are needed to determine whether lymphoscintigraphy drainage patterns identify patients at the highest risk for IMN metastases who may benefit from radiotherapy.

F plasmid conjugative DNA transfer: the TraI helicase activity is essential for DNA strand transfer.

The product of the Escherichia coli F plasmid traI gene is required for DNA transfer via bacterial conjugation. This bifunctional protein catalyzes the unwinding of duplex DNA and is a sequence-specific DNA transesterase. The latter activity provides the site- and strand-specific nick required to initiate DNA transfer. To address the role of the TraI helicase activity in conjugative DNA transfer traI mutants were constructed and their function in DNA transfer was evaluated using genetic and biochemical methods. A traI deletion/insertion mutant was transfer-defective as expected. A traI C-terminal deletion that removed the helicase-associated motifs was also transfer-defective despite the fact that the region of traI encoding the transesterase activity was intact. Biochemical studies demonstrated that the N-terminal domain was sufficient to catalyze oriT-dependent transesterase activity. Thus, a functional transesterase was not sufficient to support DNA transfer. Finally, a point mutant, TraI-K998M, that lacked detectable helicase activity was characterized. This protein catalyzed oriT-dependent transesterase activity in vitro and in vivo but failed to complement a traI deletion strain in conjugative DNA transfer assays. Thus, both the transesterase and helicase activities of TraI are essential for DNA strand transfer.

Sporotrichosis masquerading as pyoderma gangrenosum: case report and review of 19 cases of sporotrichosis.

We present the case of a 59-year-old woman who had large ulcerations on her right leg that were diagnosed initially as pyoderma gangrenosum and treated with three immunosuppressive agents (cyclosporin, prednisone and azathioprine) for 6 months. Results of a biopsy at 6 months showed numerous cigar-shaped bodies consistent with Sporothrix schenckii; identification was confirmed by tissue culture. A retrospective review was performed for all cases diagnosed as sporotrichosis from tissue culture or biopsy specimens at the Mayo Clinic. Nineteen cases were identified. The present case was the only one in which fungal organisms were visible on histological examination. The present case emphasizes the importance of making a definitive histological diagnosis in unusual ulcer cases or in suspected cases of pyoderma gangrenosum before the initiation of immunosuppressive therapy. The large number of cigar-shaped bodies in the tissue is a rare finding in sporothrix infection and has been reported in only two cases previously.

Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo.

Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previously in humans. In this study, we describe a patient with metastatic melanoma who developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1-specific CD8(+) T cell clones. Analysis of the infiltrating lymphocytes in skin and tumor biopsies using T cell-specific peptide-major histocompatibility complex tetramers demonstrated a localized predominance of MART-1-specific CD8(+) T cells (>28% of all CD8 T cells) that was identical to the infused clones (as confirmed by sequencing of the complementarity-determining region 3). In contrast to skin biopsies obtained from the patient before T cell infusion, postinfusion biopsies demonstrated loss of MART-1 expression, evidence of melanocyte damage, and the complete absence of melanocytes in affected regions of the skin. This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.

Neonatal thyroid-stimulating hormone level and perchlorate in drinking water.

BACKGROUND: The effect of perchlorate in drinking water on neonatal blood thyroid-stimulating hormone (thyrotropin; TSH) levels was examined for Las Vegas and Reno, Nevada. METHODS: The neonatal blood TSH levels in Las Vegas (with up to 15 microg/L (ppb) perchlorate in drinking water) and in Reno (with no perchlorate detected in the drinking water) from December 1998 to October 1999 were analyzed and compared. The study samples were from newborns in their first month of life (excluding the first day of life) with birth weights of 2, 500-4,500 g. A multivariate analysis of logarithmically transformed TSH levels was used to compare the mean TSH levels between Las Vegas and Reno newborns, with age and sex being controlled as potential confounders. RESULTS: This study of neonatal TSH levels in the first month of life found no effect from living in the areas with environmental perchlorate exposures of

Use of herbal therapies by adults seen in an ambulatory care research setting: an exploratory survey.

OBJECTIVE: To identify and characterize patterns of use of herbal products among patients participating in selected research clinics. DESIGN: Survey of three National Institutes of Health (NIH) ambulatory care research clinics. SUBJECTS: Convenience sample of 490 adult patients (168 male, 322 female) attending rheumatology, liver, and endocrinology/metabolic research clinics. RESULTS: Of the patients surveyed, 16.7%: (n = 82) reported using herbs. There were no significant sociodemographic differences between herb and nonherb users. Indications for herb use differed among the disease groups; patients in the endocrine and rheumatology clinics were taking herbs predominantly for "energy" or "wellness"; those attending the liver clinic tended to use herbal therapies as treatment for their disease. Mean and median monthly expenditure for herbal products was $30 and $10, respectively. There was a significant positive correlation between number of herbs used and use of other dietary supplements (p < 0.0001). CONCLUSIONS: One in six patients in ambulatory clinical research settings may be taking herbal products in addition to prescribed treatment. This figure is lower than in the general population, possibly because the patients may stop using herbs when participating in a research project. Although empirical evidence on the beneficial or adverse effects of herb therapy alone or in combination with drug therapies is limited, clinical researchers should be aware of the potential for confounding clinical trial results.

Alar batten cartilage grafting in nasal reconstruction: functional and cosmetic results.

BACKGROUND: Alar batten cartilage grafts can restore form and function to a compromised ala, prevent stenosis of the nasal valve, and maintain unrestricted air movement. Soft tissue reconstructive options can be combined with alar batten grafts. OBJECTIVE: Our purpose was to analyze functional and cosmetic outcomes in a series of patients undergoing alar batten cartilage grafting. METHODS: We analyzed the functional and cosmetic outcomes of 25 patients in whom reconstruction involved alar batten cartilage grafts. Assessment included defect characteristics, function and cosmesis (rated by physician and patient), and complications. RESULTS: Eighty-three percent of patients had good to excellent functional and cosmetic results by patient and physician assessment. Three patients were rated as having poor cosmetic results by the physician; all 3 patients graded these results as good. One episode of graft failure occurred, and recipient and donor site complications were minor. CONCLUSION: Alar batten cartilage grafts appear to be an excellent option for reconstruction of substantial alar defects.